scholarly journals S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

2021 ◽  
Vol 9 ◽  
Author(s):  
Minxia Liu ◽  
Yinyin Wang ◽  
Juho J. Miettinen ◽  
Romika Kumari ◽  
Muntasir Mamun Majumder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Calcium Binding ◽  
Copy Number ◽  
Drug Response ◽  
Patient Survival ◽  
Family Members ◽  
Proteasome Inhibitors ◽  
S100 Family ◽  
Poor Patient ◽  
S100 Gene

Despite several new therapeutic options, multiple myeloma (MM) patients experience multiple relapses and inevitably become refractory to treatment. Insights into drug resistance mechanisms may lead to the development of novel treatment strategies. The S100 family is comprised of 21 calcium binding protein members with 17 S100 genes located in the 1q21 region, which is commonly amplified in MM. Dysregulated expression of S100 family members is associated with tumor initiation, progression and inflammation. However, the relationship between the S100 family and MM pathogenesis and drug response is unknown. In this study, the roles of S100 members were systematically studied at the copy number, transcriptional and protein level with patients’ survival and drug response. Copy number analysis revealed a predominant pattern of gains occurring in S100 genes clustering in the 1q21 locus. In general, gains of genes encoding S100 family members associated with worse patient survival. However, S100 gene copy number and S100 gene expression did not necessarily correlate, and high expression of S100A4 associated with poor patient survival. Furthermore, integrated analysis of S100 gene expression and ex vivo drug sensitivity data showed significant negative correlation between expression of S100 family members (S100A8, S100A9, and S100A12) and sensitivity to some drugs used in current MM treatment, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and histone deacetylase inhibitor panobinostat. Combined proteomic and pharmacological data exhibited significant negative association of S100 members (S100A4, S100A8, and S100A9) with proteasome inhibitors and panobinostat. Clinically, the higher expression of S100A4 and S100A10 were significantly linked to shorter progression free survival in patients receiving carfilzomib-based therapy. The results indicate an association and highlight the potential functional importance of S100 members on chromosome 1q21 in the development of MM and resistance to established myeloma drugs, including proteasome inhibitors.

scholarly journals Increased TPSAB1 Copy Number in a Family With Elevated Basal Serum Levels of Tryptase

2021 ◽  
Vol 8 ◽  
Author(s):  
Laura Hernández-Hernández ◽  
Catalina Sanz ◽  
Elena Marcos-Vadillo ◽  
Asunción García-Sánchez ◽  
Esther Moreno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Copy Number ◽  
Family Members ◽  
Copy Number Gain ◽  
Digital Pcr ◽  
Gene Dose ◽  
Control Subjects ◽  
Basal Serum ◽  
The Family

Background: Some recent familial studies have described a pattern of autosomal dominant inheritance for increased basal serum tryptase (BST), but no correlation with mRNA expression and gene dose have been reported.Objective: We analyzed TPSAB1 mRNA expression and gene dose in a four-member family with high BST and in two control subjects.Methods: Blood samples were collected from the family and control subjects. Complete morphologic, immunophenotypical, and molecular bone marrow mast cell (MC) studies were performed. mRNA gene expression and gene dose were performed in a LightCycler 480 instrument. Genotype and CNV were performed by quantitative real-time digital PCR (qdPCR).Results: CNV analysis revealed a hereditary copy number gain genotype (3β2α) present in all the family members studied. The elevated total BST in the family members correlated with a significant increase in tryptase gene expression and dose.Conclusions and Clinical Relevance: We present a family with hereditary α-tryptasemia and elevated BST which correlated with a high expression of tryptase genes and an increased gene dose. The family members presented with atypical MC-mediator release symptoms or were even asymptomatic. Clinicians should be aware that elevated BST does not always mean an MC disorder.

Good and Poor Response Gene Expression Signatures to Proteasome Inhibitors Using a Mouse Model of Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1843-1843
Author(s):  
Holly Stessman ◽  
Linda B. Baughn ◽  
Aaron G. Sarver ◽  
Aatif Mansoor ◽  
Tzu G. Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Copy Number ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Gene Signature ◽  
Mouse Tumor ◽  
Tumor Cell Lines

Abstract Abstract 1843 The proteasome inhibitor bortezomib (Bz) has been used extensively and with much success in the treatment of multiple myeloma (MM) patients; however, patients eventually relapse, many as non-responders to subsequent treatments with Bz making drug resistance a significant problem. Here we utilized cell lines created using a iMycCa/Bcl-xL transgenic mouse model of MM (Cheung, et al. J Clin Invest (2004) 113: 1763) to identify 1) gene expression signatures of Bz response, 2) differences in gene expression between sensitive and resistant cell lines, and 3) cytogenetic abnormalities associated with Bz sensitive and resistant phenotypes. The iMycCa/Bcl-xL transgenic mice develop plasma cell tumors with 100% penetrance and have shown strikingly strong similarities to human MM by extensive gene expression profiling (GEP), spectral karyotyping and histology (Boylan, et al. Cancer Res (2007) 67: 4069). Six cell lines created from these mice were dose escalated with Bz over approximately six months to create Bz resistant (BzR) cell lines with approximately 5–8 fold increase in IC50 to Bz compared to their sensitive counterparts. The BzR characteristics were stable, as lines grown in the absence of drug for as long as 6 months maintained drug resistance upon subsequent challenge. Notably, BzR lines showed cross resistance to other investigational proteasome inhibitors (MLN9708 and carfilzomib) while maintaining sensitivity to other chemotherapeutic agents (dexamethasone and melphalan), suggesting a common mechanism of emerging resistance to proteasome inhibitors. The results of GEP of these mouse tumor cell lines treated with Bz were compared with a recently published human drug trial where GEP was completed prior to and 48 hours after a “test dose” of Bz was administered to patients (Shaughnessy, et al. Blood (2011), ahead of print). In the mouse tumor cell lines, 116 genes were differentially expressed upon in vitro Bz treatment (p=0.001, ≥1.5 fold change). Between the mouse and human drug response data sets was an overlapping common 27-gene signature (p=1×10−25, Fishers exact test) of Bz-induced expression changes that has not previously been described. Time points were collected in these mouse cell line GEP experiments at 0, 2, 8, 16, and 24 hours after Bz treatment. A comparison of the Bz sensitive and derived BzR lines prior to drug treatment revealed a 50 gene signature (p=0.05, ≥2 fold change) that distinguishes three pairs of sensitive and resistant lines. Gene-set enrichment analyses have revealed significant pathways that are differentially regulated in the sensitive and resistant responses. Additional GEP differences were seen when time course expression patterns were examined from Bz sensitive compared to resistant tumor lines. Thus, GEP signatures that distinguish tumor lethality from resistance were identified both prior to Bz treatment, as well as in the early response to Bz. In addition, array comparative genomic hybridization on 4 pairs of mouse Bz sensitive and established BzR lines revealed not only gross differences in copy number between the differentially responding groups of cells but copy number abnormalities that may be unique to the emerging resistance. Taken together, these data indicate that this model is useful for the identification of good and poor Bz response signatures in MM. These signatures are currently being evaluated in human tumor cells from single agent bortezomib phase II and phase III clinical trials. Because the in vitro adapted tumor mouse lines can be genetically manipulated using lentiviral vectors, this model can be used as a preclinical platform to validate existing gene models with respect to Bz response, something that cannot be done using human patients. Subsequent transfer of manipulated lines into syngeneic, immunocompetent recipients can further test Bz response in vivo presenting a significant advantage of this robust mouse MM model system over other in vitro systems. Disclosures: Stessman: Millennium: The Takeda Oncology Company: Research Funding. Mansoor:Millennium: The Takeda Oncology Company: Research Funding. Janz:Millennium: The Takeda Oncology Company: Research Funding. Van Ness:Millennium: The Takeda Oncology Company: Research Funding.

Copy number increase of oncoprotein CIP2A is associated with poor patient survival in human head and neck squamous cell carcinoma

2015 ◽  
Vol 45 (5) ◽  
pp. 329-337 ◽  
Author(s):  
Johannes Routila ◽  
Türker Bilgen ◽  
Outi Saramäki ◽  
Reidar Grénman ◽  
Tapio Visakorpi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Copy Number ◽  
Patient Survival ◽  
Human Head ◽  
Poor Patient ◽  
Number Increase ◽  
Copy Number Increase ◽  
Poor Patient Survival

scholarly journals Friend or Foe: S100 Proteins in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2037 ◽  
Author(s):  
Chantal Allgöwer ◽  
Anna-Laura Kretz ◽  
Silvia von Karstedt ◽  
Mathias Wittau ◽  
Doris Henne-Bruns ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Family Members ◽  
S100 Proteins ◽  
S100 Family ◽  
Cellular Processes ◽  
Ef Hand ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment.

scholarly journals Evaluation of colorectal cancer subtypes and cell lines using deep learning

2018 ◽  
Author(s):  
Jonathan Ronen ◽  
Sikander Hayat ◽  
Altuna Akalin
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Deep Learning ◽  
Drug Discovery ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Response ◽  
Latent Factors ◽  
Cancer Models ◽  
Selection Of

ABSTRACTColorectal cancer (CRC) is a common cancer with a high mortality rate and a rising incidence rate in the developed world. The disease shows variable drug response and outcome. Molecular profiling techniques have been used to better understand the variability between tumours as well as cancer models such as cell lines. Drug discovery programs use cell lines as a proxy for human cancers to characterize their molecular makeup and drug response, identify relevant indications and discover biomarkers. In order to maximize the translatability and the clinical relevance of in vitro studies, selection of optimal cancer models is imperative. We have developed a deep learning based method to measure the similarity between CRC tumors and other tumors or disease models such as cancer cell lines. Our method efficiently leverages multi-omics data sets containing copy number alterations, gene expression and point mutations, and learns latent factors that describe the data in lower dimension. These latent factors represent the patterns across gene expression, copy number, and mutational profiles which are clinically relevant and explain the variability of molecular profiles across tumours and cell lines. Using these, we propose a refined colorectal cancer sample classification and provide best-matching cell lines in terms of multi-omics for the different subtypes. These findings are relevant for patient stratification and selection of cell lines for early stage drug discovery pipelines, biomarker discovery, and target identification.

scholarly journals Comprehensive Analysis of the Prognosis of S100 Family Members and Their Relationship with Tumor-Infiltrating Immune Cells in Human Pancreatic Adenocarcinoma

2021 ◽  
Author(s):  
Yajun Ren ◽  
Bing Chen ◽  
Meng Zhang ◽  
Feng Xu
Keyword(s):  
Mrna Expression ◽  
Pancreatic Adenocarcinoma ◽  
Immune Cells ◽  
Calcium Binding ◽  
Expression Patterns ◽  
Family Members ◽  
Tumor Stage ◽  
Risk Models ◽  
S100 Family ◽  
Ef Hand

Abstract Background: S100 family members(S100s) are small molecular EF hand calcium binding proteins and widely expressed in many tissues and organs. S100s are shown to be biomarkers of disease progression and prognosis in various types of cancers. Nevertheless, the expression patterns, function, prognostic values of S100s and its association with tumor-infiltrating immune cells in Pancreatic Adenocarcinoma(PAAD) patients have not been systematically clarified. Methods: we explored that the expression and roles of the entire twenty S100s in PAAD patients by using the following public databases: Oncomine, GEPIA, cBioPortal, Metascape, STRING, TIMER and GeneMANIA.Results: The S100A2/A3/A4/A6/A8/A9/A10/A11/A13/A14/A16/B/P mRNA expression were significantly upregulated in PAAD patients. The mRNA expression of S100A3/A4/A5/A6/A10/A11/A14/A16/Z were significantly negatively related with the tumor stage in PAAD patients. We found that the S100A2/A3/A5/A10/A11/A14/A16 were significantly correlated with poor OS, whereas the increased levels of S100A1/B/G/Z were strongly associated with good OS. We found significant correlations among S100s and Tumor-Infiltrating Immune Cells. Cox proportional risk models revealed that B cells, Dendritic cells and S100A1/A5/A6/A8/A9/A13/A14 were significantly related with outcomes in PAAD patients. Conclusions: S100A2/A3/A10/A11/A14/A16 may serve as new diagnostic and prognostic biomarkers for PAAD patients and provide new clues for immunotherapy in PAAD patients.

scholarly journals Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1008
Author(s):  
Benjamin C. Shaw ◽  
Yuriko Katsumata ◽  
James F. Simpson ◽  
David W. Fardo ◽  
Steven Estus
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Copy Number ◽  
Gene Deletion ◽  
Association Studies ◽  
Family Members ◽  
Genome Wide Association Studies ◽  
Complex Genetics ◽  
Genome Wide

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent GWAS. We found that pQTLs for genes encoding ITIM/ITAM family members were more frequently associated with AD than those for non-ITIM/ITAM genes. Further testing of one family member, SIGLEC14 which encodes an ITAM, uncovered substantial copy number variations, identified an SNP as a proxy for gene deletion, and found that gene expression correlates significantly with gene deletion. We also found that SIGLEC14 deletion increases the expression of SIGLEC5, an ITIM. We conclude that many genes in this ITIM/ITAM family likely impact AD risk, and that complex genetics including copy number variation, opposing function of encoded proteins, and coupled gene expression may mask these AD risk associations at the genome-wide level.

scholarly journals Systematic computational identification of prognostic cytogenetic markers in neuroblastoma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Chao Qin ◽  
Xiaoyan He ◽  
Yanding Zhao ◽  
Chun-Yip Tong ◽  
Kenneth Y. Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Proportional Hazards ◽  
Patient Survival ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Models ◽  
Gain Loss ◽  
Chromosome Bands

Abstract Background Neuroblastoma (NB) is the most common extracranial solid tumor found in children. The frequent gain/loss of many chromosome bands in tumor cells and absence of mutations found at diagnosis suggests that NB is a copy number-driven cancer. Despite the previous work, a systematic analysis that investigates the relationship between such frequent gain/loss of chromosome bands and patient prognosis has yet to be implemented. Methods First, we analyzed two NB CNV datasets to select chromosomal bands with a high frequency of gain or loss. Second, we applied a computational approach to infer sample-specific CNVs for each chromosomal band selected in step 1 based on gene expression data. Third, we applied univariate Cox proportional hazards models to examine the association between the resulting inferred copy number values (iCNVs) and patient survival. Finally, we applied multivariate Cox proportional hazards models to select chromosomal bands that remained significantly associated with prognosis after adjusting for critical clinical variables, including age, stage, gender, and MYCN amplification status. Results Here, we used a computational method to infer the copy number variations (CNVs) of sample-specific chromosome bands from NB patient gene expression profiles. The resulting inferred CNVs (iCNVs) were highly correlated with the experimentally determined CNVs, demonstrating CNVs can be accurately inferred from gene expression profiles. Using this iCNV metric, we identified 58 frequent gain/loss chromosome bands that were significantly associated with patient survival. Furthermore, we found that 7 chromosome bands were still significantly associated with patient survival even when clinical factors, such as MYCN status, were considered. Particularly, we found that the chromosome band chr11p14 has high potential as a novel candidate cytogenetic biomarker for clinical use. Conclusion Our analysis resulted in a comprehensive list of prognostic chromosome bands supported by strong statistical evidence. In particular, the chr11p14 gain event provided additional prognostic value in addition to well-established clinical factors, including MYCN status, and thereby represents a novel candidate cytogenetic biomarker with high clinical potential. Additionally, this computational framework could be readily extended to other cancer types, such as leukemia.

Transcriptional profiling of iPSC-derived neurons with reciprocal monogenic CNV in 3p26.3 region

2020 ◽  
pp. 10-11
Author(s):  
М.Е. Лопаткина ◽  
В.С. Фишман ◽  
М.М. Гридина ◽  
Н.А. Скрябин ◽  
Т.В. Никитина ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
System Development ◽  
Transcriptional Profiling ◽  
Global Gene Expression ◽  
Nervous System Development ◽  
Number Variation ◽  
The Central Nervous System ◽  
Cntn6 Gene ◽  
Copy Number Changes

Проведен анализ генной экспрессии в нейронах, дифференцированных из индуцированных плюрипотентных стволовых клеток пациентов с идиопатическими интеллектуальными нарушениями и реципрокными хромосомными мутациями в регионе 3p26.3, затрагивающими единственный ген CNTN6. Для нейронов с различным типом хромосомных аберраций была показана глобальная дисрегуляция генной экспрессии. В нейронах с вариациями числа копий гена CNTN6 была снижена экспрессия генов, продукты которых вовлечены в процессы развития центральной нервной системы. The gene expression analysis of iPSC-derived neurons, obtained from patients with idiopathic intellectual disability and reciprocal microdeletion and microduplication in 3p26.3 region affecting the single CNTN6 gene was performed. The global gene expression dysregulation was demonstrated for cells with CNTN6 copy number variation. Gene expression in neurons with CNTN6 copy number changes was downregulated for genes, whose products are involved in the central nervous system development.

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